A number of recent studies both in murine model systems and in hepatitis B virus (HBV)-infected patients indicate the importance of the immune response to the nucleocapsid antigens of the HBV in the induction and/or maintenance of chronic infection. Therefore, the purpose of this application is a detailed analysis of the immune responses to the particulate hepatitis B core antigen (HBcAg) and the secreted non- particulate form of the nucleocapsid, namely the HBeAg. This analysis will include: (1) establishing HBeAg-expressing transgenic (Tg) mice as a model of HBeAg/anti-HBe seroconversion in chronic HBV infection and a model in which to screen immunotherapeutic protocols; (2) use of novel immunoassays to examine serological and cellular responses to the nucleocapsid antigens in HBV-infected patients; (3) exploration of the importance of Th1 and Th2 cell subsets in the immune response to HBV nucleocapsid antigens and their possible role in chronicity; (4) analysis of the unique features of antigen presentation of the HBV nucleocapsid antigens to The cells and its possible role in chronicity; and (5) production of HBc/eAg-specific T cell receptor (TCR) transgenic mice and dual Tg mice expressing the HBc/eAgs as well as TCRs specific for these antigens. Although the specific aims represent basic and applied approaches, each project has been designed to answer questions relevant to chronic HBV infection. For example, does T cell tolerance play a role in chronic HBV infection? Do the enhanced humoral immune responses and relatively weak cellular responses observed in HBV chronic carriers reflect an imbalance in Th1 -Th2 cell subsets? If so, can the Th1 -Th2 imbalance be corrected in vivo? Does the enhanced immunogenicity of the HBcAg derive from entry into a specialized antigen presentation pathway? What effect does maternal anti-HBc have on the neonates HBcAg-specific The cell response? It is anticipated that the results of these studies will have diagnostic, therapeutic, and vaccine applications and will provide a better understanding of basic immune mechanisms responsible for viral persistence and clearance in chronic and acute HBV infection.